Oral-Gut-Brain Axis in Experimental Models of Periodontitis: Associating Gut Dysbiosis With Neurodegenerative Diseases

Abstract

Periodontitis is considered a non-communicable chronic disease caused by a dysbiotic microbiota, which generates a low-grade systemic inflammation that chronically damages the organism. Several studies have associated periodontitis with other chronic non-communicable diseases, such as cardiovascular or neurodegenerative diseases. Besides, the oral bacteria considered a keystone pathogen, Porphyromonas gingivalis, has been detected in the hippocampus and brain cortex. Likewise, gut microbiota dysbiosis triggers a low-grade systemic inflammation, which also favors the risk for both cardiovascular and neurodegenerative diseases. Recently, the existence of an axis of Oral-Gut communication has been proposed, whose possible involvement in the development of neurodegenerative diseases has not been uncovered yet. The present review aims to compile evidence that the dysbiosis of the oral microbiota triggers changes in the gut microbiota, which creates a higher predisposition for the development of neuroinflammatory or neurodegenerative diseases.The Oral-Gut-Brain axis could be defined based on anatomical communications, where the mouth and the intestine are in constant communication. The oral-brain axis is mainly established from the trigeminal nerve and the gut-brain axis from the vagus nerve. The oral-gut communication is defined from an anatomical relation and the constant swallowing of oral bacteria. The gut-brain communication is more complex and due to bacteria-cells, immune and nervous system interactions. Thus, the gut-brain and oral-brain axis are in a bi-directional relationship. Through the qualitative analysis of the selected papers, we conclude that experimental periodontitis could produce both neurodegenerative pathologies and intestinal dysbiosis, and that periodontitis is likely to induce both conditions simultaneously. The severity of the neurodegenerative disease could depend, at least in part, on the effects of periodontitis in the gut microbiota, which could strengthen the immune response and create an injurious inflammatory and dysbiotic cycle. Thus, dementias would have their onset in dysbiotic phenomena that affect the oral cavity or the intestine. The selected studies allow us to speculate that oral-gut-brain communication exists, and bacteria probably get to the brain via trigeminal and vagus nerves.

Keywords: Alzheimer’s disease; dysbiosis; gut microbiota; keystone; pathogen; periodontitis.

FIGURE 1

Enterochromaffin cell role in the oral-gut communication. During an oral dysbiosis, the increase in anaerobic bacteria associated with periodontitis produces an increase in the swallowed bacterial load. These bacteria, upon reaching the intestine, can generate an imbalance in the gut microbiota. One of the cells that is capable of recognizing both its own bacteria and bacteria that are relevant to the gut microbiota are the enterochromaffin. These cells possess a series of surface receptors, such as TLR2, TLR4, GABA, ChR, α2-AR, and β2-AR, which allows this cell to respond to a wide variety of bacteria, their virulence factors or even, the neurotransmitters that some of them produce. In this way, normobiosis or dysbiosis differentially activates enterochromaffin cells, which through glutamate or serotonin stimulate efferent vagal neurons to have an associated response. TLR: Toll Like Receptor, GABA: γ-Amino Butyric Acid, ChR: Cholinergic receptor, α2-Adrenergic Receptor, β2-Adrenergic Receptor, NE: Nor-Epinephrin, Ep: Epinephrin, IL: Interleukin, TNF: Tumoral Necrosis Factor.

FIGURE 2

Oral dysbiosis induce gut dysbiosis, intestinal barrier permeabilization and intestinal inflammation. During intestinal dysbiosis caused by periodontal anaerobic bacteria, there is an alteration in the Bacteroidales spp and Firmicutes spp rate. Intestinal dysbiosis produces an alteration in SCFA, increasing acetate and propionate and decreasing butyrate. This alteration can induce an activation of the inflammatory response in macrophages and neutrophils. As a consequence, dysbiosis triggers the permeabilization of the intestinal barrier by the rearrangement of the adherent junctions. This reorganization implies a modification in the location and number of these junctions, which allows bacteria or their virulence factors to enter the submucosa. Once in the submucosa, the primary cells of the immune system will engulf the bacteria and respond by secreting pro-inflammatory cytokines. Depending on the bacterial load or virulence factors that are entering, the primary immune cells may secrete chemokines, which attract dendritic cells. Dendritic cells will engulf the antigen, process it, internalize it, and present to CD4⁺ T lymphocytes in Peyer’s patches or regional lymph nodes. Subsequently and, depending on the antigen presented, the clonal expansion and differentiation of the CD4⁺ T lymphocytes to the different effector phenotypes will occur. The presence of Th1 and Th17 lymphocytes will be associated with a higher pro-inflammatory response and permeabilization of the intestinal barrier. Evidence suggests that the presence of Th22 lymphocytes and IL-22 would influence the proliferation of anaerobic bacteria, participating in the modulation of the permeabilization of the barrier. In addition, the presence of Treg lymphocytes will decrease the inflammatory response, allowing the recovery of intestinal homeostasis. Indeed, during normobiosis, bacteria or their factors can be internalized into the submucosa by the epithelial cells themselves and, when recognized by the primary immune cells, differentiate into modulating phenotypes. This modulating response is characterized by the secretion of modulating or regulatory cytokines such as IL-10 or TGF-β1. Dendritic cells will be able to recognize antigens and present them to T or B lymphocytes, which will proliferate and differentiate into Treg lymphocytes or plasma cells, which will modulate the intestinal response, maintaining homeostasis. SCFA: Short chain fat acids, Th: T helper lymphocytes, Treg: T regulatory lymphocytes, IL: Interleukin, TGF-β1: Transforming growth factor β1, TNF: tumor necrosis factor, iDCs: immature dendritic cells, mDCs: mature dendritic cells, IgA: Immunoglobulin A, ROS: reactive oxygen species.

FIGURE 3

Gut-Brain neuroimmune communication. The network of neurons that innervates the intestine involves a series of neurons with different locations and functions. Secretory motor neurons, primary intrinsic afferent neurons, and vasomotor neurons are located in the submucosal plexus. In the myenteric plexus, the interneurons, the inhibitory, excitatory, secretory motor, and the intrinsic primary afferent neurons are located, in addition to the glia. In both the submucosal and myenteric plexus there are resident macrophages and neutrophils. In particular, myenteric plexus macrophages have the ability to migrate to the submucosa and regulate the neuronal and immune response induced by changes in the gut microbiota or food ingestion. Besides, the B cells can generate humoral responses at the myenteric plexus level. Finally, in the longitudinal musculature there are interstitial neurons. In this way, changes in the lumen are sensed by immune cells or neurons present in the mucosa and submucosa, and are regulated by neurons and immune cells located in the myenteric plexus.

FIGURE 4

Oral-Brain axis components. (A) During periodontitis, possible transient bacteremia could induce atherogenesis at the brain level. Macrophages and endothelial cells associated with atheroma plaque can produce pro-inflammatory mediators, which spread to the brain. There, it produces functional changes both in the astrocyte of the neurovascular unit and in the microglia. Both cells, in response to local inflammation, will produce IL-1β, IL-6, IL-17, and TNF-α and, together with MMP2 and MMP9, will produce an exacerbation of inflammation and degradation of the proteins of the neurovascular unit. In this way, a breakout of the BBB will occurs. Then, the inflammation induced by microglia and reactive astrocytes will affect neuronal function, generating the necessary stimuli for the production of amyloid β and hyperphosphorylation of the Tau protein. In this way, the BBB breakdown may produce senile plaques, NFTs, and neuronal death. (B) The fibers of the trigeminal nerve that innervate the periodontal tissues have various surface receptors that can recognize LPS, capsular polysaccharides, fimbria, among other virulence factors. The activation of these receptors (TLRs, CDs, and TRPV1) can induce the activation of NF-κB, the formation of the phagosome or the increase of intracellular Ca+2. In response, the neuron will respond by producing IL-1β, IL-6, and TNF-α in the trigeminal ganglion. Furthermore, in the trigeminal ganglion there are glial cells that are capable of recognizing bacteria, engulfing, processing, and presenting them to the CD4⁺ T lymphocytes in the trigeminal ganglion. Pathogenic bacteria that have the ability to inhibit phage-lysosome formation can remain alive within the phagosome and, through vesicular trafficking, can move along the axon or dendrites of the neuron. Thus, this could be a possible bacterial migration pathway. Furthermore, neurons that recognize pathogenic bacteria could secrete pro-inflammatory cytokines in the trigeminal pontine nucleus or in other areas of the brain, and generate activation in microglia and astrocytes. (C) The lymphatic pathway is made up of antigen-presenting cells that recognize, incorporate, and process pathogenic bacteria, and migrate to the regional lymph node to present the antigen. In the regional lymph node they can present CD4⁺ T lymphocytes, which depending on the context, will differentiate into the different effector phenotypes. Certain pathogenic bacteria have the ability to inhibit phage-lysosome formation and thus survive and migrate utilizing host cell migration mechanisms. In this way, once in the lymph node, the phagocytes could migrate to another lymph node or, the bacteria could migrate through the lymphatic vessels to another lymphatic site. In particular, the III and IV cerebral ventricle drains, as do the submandibular or parotid lymph nodes, to the deep mid-cervical cervical. Therefore, the oral cavity and the brain would be lymphatically connected. IL: interleukin, TNF: tumor necrosis factor, MMP: matrix metalloproteinases, BBB: blood-brain barrier, LPS: lipopolysaccharide, TLRs: toll-like receptors, CDs: cluster of differentiation, TRPV1: transient receptor potential cation channel V1, NF-κB: nuclear factor κ B, NFTs: neurofibrillary tangles, TCR: T-cell receptor, HLA: human-leukocyte antigens, ROS: reactive oxygen species.

FIGURE 5

Nervous system in bone biology. Pre-osteoclast and osteoclasts possess α2-adrenergic, β2-adrenergic, substance P, and calcitonin gene related peptide surface receptors. Although, the presence of RANKL is capable of allowing the activation of osteoclasts to allow the fusion of precursors, the evidence suggests the role of epinephrine, nor-epinephrine, substance P and the calcitonin gene related peptide in regulating both of formation as bone resorption. In a pro-inflammatory context, the presence of nor-epinephrin and epinephrin will produce an increase in osteoclast function and a decrease in osteoblastic function, by decreasing the pre-osteoclast activation. On the contrary, in the presence of substance P or calcitonin gene related peptide, the effect will be higher for bone formation and bone resorption will decrease. Thus, under a distress response, the epinephrine will be activating constantly the pre-osteoclasts and osteoclasts. Osteoclasts will increase their bone-resorptive function by secreting HCl, collagenases (MMP8 and MMP13) and gelatinases (MMP2 and MMP9). Pre-OC: pre-osteoclast, PC: octeoclast, α-AR: α2-Adrenergic receptor, β-AR: β2-Adrenergic receptor: SP-R: substance P receptor, GRCP-R: gene-related with calcitonin peptide receptor, OPG. Osteoprotegerin, RANKL: Receptor of the activator of nuclear factor κB ligand, RANK: Receptor of the activator of nuclear factor κB, IL: interleukin, MMP: matrix metalloproteinases.

FIGURE 6

Oral-gut-brain axis. During periodontitis, the exacerbated increase in anaerobic bacteria generates alterations in the intestinal microbiota. First, swallowed oral bacteria are significantly increased. These bacteria can survive the stomach pH and upon reaching the intestine, they can cause intestinal dysbiosis, alteration in the integrity of the intestinal barrier and inflammation. This effect will cause virulence factors or pro-inflammatory mediators to diffuse into the peripheral circulation and thus migrate to the brain. In addition, oral dysbiotic bacteria can migrate to the brain via the trigeminal nerve endings or through the lymphatic vessels. Another possible route of migration is through the fibers of the vagus nerve that innervate the intestine. Thus, the possible routes of migration of oral bacteria to the brain can be through oral-brain communication or through gut-brain communication. Thus, periodontitis could be associated with neuroinflammatory events by direct communication with the brain or, indirectly, by altering intestinal homeodynamics.